Risk is an inherent part of every drug development project. Pharmaceutical companies face financial risks, regulatory risks, market risks, and most importantly – patient safety risks. Figuring out how a drug will impact patients across the spectrum of target users, and whether it is safe for all potential patients, is a vital step in validating its safety and efficacy. Which is why risk management planning has become an important part of the drug approval process.
Medication risk management plans, which are known as Risk Evaluation and Mitigation Strategies (REMS) in the US, and Risk Management Plans (RMPs) in the EU, have been embedded in the regulatory system
for more than a decade as a way to ensure that the benefits of a drug outweigh its risks by as much as possible. A drug which has more risk than benefit will never be approved, but risk management may reduce the risks of a drug to the extent that the benefit/risk profile becomes positive. Risk management plans require manufacturers to examine what is known and not known about a drug or treatment in order to plan further research and clarify the safety and risk factors associated with the drug. Whereas most drugs have risk minimization via the approved label, there are cases in which a particular sub-group of patients might respond differently than the studied population. In these cases, risk management plans include specific additional mitigation steps that enable regulators to allow otherwise promising drugs to be used by patients.
Birth defects and PML
While they do require added time and effort, REMS and RMPs can be a valuable safety strategy for biopharmaceutical companies. By doing the necessary research required by a risk management plan, and putting in place risk minimization strategies, manufacturers can minimize the impact of potential deadly consequences related to use of their drug, while still being able to bring it to market to serve an unmet medical need.
One of the most well-known examples
related to risk management is thalidomide, a drug that caused more than 10,000 serious birth defects in the 1960s when women took it to control nausea. The drug was not approved by the FDA at that time, but in 1998 FDA did approve it to treat leprosy and multiple myeloma. As part of that approval process, a REMS was developed to ensure that pregnant women were not exposed to the drug. In this way, those patients at risk from serious side effects were protected, while allowing the drug to be used by patients who can benefit from the treatment.
In another case
, FDA approved Biogen Idec’s Tysabri
(natalizumab) for treatment of patients with multiple sclerosis and Crohns Disease. After approval, it was discovered in certain cases to cause progressive multifocal leukoencephalopathy (PML), a rare brain infection that frequently leads to death or severe disability. Investigation of the PML cases, and the patients taking the drug who did not develop PML, identified risk factors which were used to develop a REMS action plan. This action plan allowed the drug to be reintroduced by FDA with a restrictive distribution program that includes blood tests for JCV and other risk management steps as part of the treatment protocol. Tysabri was under evaluation at the EMA when PML became an issue and the development of a robust RMP allowed the drug to receive a marketing authorization. The risk minimization plan has been progressively modified as more information about risk factors became available from research and this illustrates that risk management is constantly evolving to maximize the benefit risk balance for patients.
Embrace the risk process
In the US, FDA requires a REMS only if they determine that it is necessary in a particular circumstance to ensure the benefits of the drug or biological product outweigh its risks. In the EU, the EMA requires an RMP
as part of the approval for any new product, or for some approved products when new safety information arises. A new indication will also frequently trigger the need for either a new, or an updated, RMP.
While I am not sure that requiring RMPs for every new drug, especially generics, is necessarily a good use of scarce pharmacovigilance resources, RMPs in some cases can be a useful catalyst for regulators and the pharma industry to delve more deeply into the risks associated with an innovative medicine coming to market. The process of building a risk management plan for a drug forces pharmaceutical companies to ask new questions about their data and to explore what they know and what they don’t know about that drug. These answers can be used to pursue additional research, and more closely examine the effectiveness and safety of the drug in real world settings.
Manufacturers should start thinking about their post-authorization development plan as early as Phase II of the development process. Planning an integrated development plan can save time and money, and integrating evidence generation from clinical trials and real world observational studies enables a smooth transition across the life-cycle of the medicine. Asking risk-related questions sooner and more frequently throughout the project lifecycle will help researchers make more informed decisions, and pursue the necessary avenues of research, including real world studies, to accommodate a wide variety of stakeholder demands – including that of regulators. By making risk management plans an integral part of the development process - rather than a task tacked on at the end - they can reduce their own risks of unnecessary delays to the approval process and speed their ability to bring new drugs to market.
Looking ahead, having such data in place sooner in the trial process may also enable some manufacturers to secure early licensing based on proven efficacy and robust risk minimization. Right now that is just a vision for the future, but if it becomes a reality, those companies that have established strong risk management practices, including robust post-authorization development plans, will be best positioned to make the most of such fast track opportunities.